The present study was directed toward determining the role of the kidney in the metabolism of various classes of serum proteins and to define the urinary protein excretion patterns and the pathogenesis of disorders of protein metabolism in patients with proteinuria. To this end, the metabolic fates of a small protein, lambda-L chain (mol wt 44,000), and a protein of intermediate size, IgG (mol wt 160,000), were studied in controls and patients with renal disease. Controls metabolized 0.28%/hr of circulating IgG and 22.3%/hr of circulating lambda-L chain. All the IgG and 99% of the lambda-L chain was catabolized with the remaining lambda-L chain lost intact into the urine. The kidney was shown to be the major site of catabolism for small serum proteins. Three distinct disorders of protein metabolism were noted in patients with renal tubular disease and tubular proteinuria, glomerular disease (the nephrotic syndrome), and disease involving the entire nephrons (uremia), respectively. Patients with renal tubular disease had a 50-fold increase in the daily urinary excretion of 15-40,000 molecular weight proteins such as lysozyme and lambda-L chains. Serum IgG and lambda-L chain survivals were normal; however, the fraction of the over-all lambda-L chain metabolism accounted for by proteinuria was increased 40-fold whereas endogenous catabolism was correspondingly decreased. Thus, tubular proteinuria results from a failure of proximal tubular uptake and catabolism of small proteins that are normally filtered through the glomerulus. Patients with the nephrotic syndrome had a slight increase in lambda-L chain survival whereas IgG survival was decreased and the fraction of IgG lost in the urine was markedly increased. Here, abnormal glomerular permeability to proteins of intermediate size is the basic abnormality. Patients with uremia had a normal IgG survival but a four to 10-fold prolongation of lambda-L chain survival due to loss of entire nephrons, the major site of metabolism of these proteins. This results in an increase (up to 10-fold) in the serum concentration of lambda-L chain, lysozyme, and other small biologically active proteins, a phenomenon that may be of importance in causing some of the manifestations of the uremic syndrome.